HYPOTHALAMO PITUITARY GONADAL AXIS Physiology of the HPG axis Endogenous opioids and the HPG axis (exerciseinduced menstrual disturbances) Effects of the immune system on the HPG axis (cytokines: interleukins and tumor necrosis factor) Hypogonadotrophic hypogonadism : hyperprolactinemia
HYPOTHALAMUS LHRH : decapeptide (pattern of administration crucial for pituitary response : pulsatile vs continuous administration) PITUITARY LH, FSH : glycoproteins composed of 2 chains : α, β α chains are identical β chains are specific for each hormone β chains are biological active
HYPOTHALAMUS LHRH : decapeptide (pattern of administration crucial for pituitary response : pulsatile vs continuous administration) PITUITARY LH, FSH : glycoproteins composed of 2 chains : α, β α chains are identical β chains are specific for each hormone β chains are biological active
GONADS Sex steroids Estrogens Progestins Androgens Gonadal protein hormones inhibins - activins + modulating FSH Follistatins -
ENDOGENOUS OPIOIDS AND MENSTRUAL CYCLE DISTURBANCES
CONCLUSIONS Exercise training frequently induces anovulatory menstrual cycles due to an increase in endogenous opioids Exercise-induced amenorrhoea increases the risk of long-term osteoporosis, and may reflect overtraining A decrease in percentage body fat inhibits GnRH through LEPTIN
ENDOGENOUS OPIOIDS DURING PREGNANCY
CYTOKINES : Polypeptides produced by cells from the immune system (macrophages, monocytes, lymphocytes) interleukins Tumor necrosis factor α Interferon Cytokines are not only produced within the immune cells but also within : Brain (astrocytes, glial cells, neurones (?) Hypothalamus Pituitary gland Adrenal gland Gonads Thyroid gland
PATHOLOGIES OF THE PITUITARY AND HYPOGONADISM
PITUITARY ADENOMAS - Prolactinomas (PRL) ~ 50 % - Growth hormone (Acromegaly) ~ 20 % - ACTH (Cushing) ~ 10 % - TSH, LH-FSH, Alpha-subunit rare - Non functional tumors ~ 15-20 %
PITUITARY ADENOMAS Endocrine effects : hyperfunction hypofunction both combined Mass effect : compression of surrounding structures (neurological, pituitary)
SYMPTOMS OF MASS EFFECTS - Headache - Visual field defects : - superior temporal quadranopsia - bitemporal hemianopsia - Ophtalmology : lateral extension of adenomas into the cavernous sinus compromising function of III, IV and VI cranial nerve diplopia - Rinorrhea - Pituitary insufficiency
PROLACTINOMA The most frequent pituitary adenoma : ~ 50 % : microadenoma (<10 mm) : 50 % : macroadenoma (>10 mm) : more frequent
CLINICAL FEATURES IN WOMEN The classical manifestations of PRL excess : - amenorrhea and galactorrhea The gonadal dysfunction can produce any menstrual cycle dysfunction (amenorrhea, oligomenorrhea with anovulation, infertility) Estrogen deficiency may result in - decreased vaginal lubrification - decreased libido - osteopenia
CLINICAL FEATURES IN MEN Galactorrhea is significantly less frequent than in women Hypogonadism is responsible : - decreased libido - impotence - infertility - loss of axillary, facial, chest and pubic hair - slight testicular atrophy - gynecomasty
DOES HYPERPROLACTINEMIA ALWAYS MEAN THE PRESENCE OF A PROLACTINOMA?
CAUSES OF HYPERPROLACTINAEMIA (I) Physiological Pharmacological Pathological Idiopathic Other causes
CAUSES OF HYPERPROLACTINAEMIA (II) Physiological Pregnancy Nursing Nipple stimulation Stress (physical, psychological, hypoglycemia) Exercice Food intake Sleep
CONDITIONS FOR BLOOD SAMPLING IN CASE OF SUSPECTED HYPERPROLACTINAEMIA Blood sampling : - in a fasting state - between 8h and 12h - take 2-3 blood samples at 30 min intervals (stress)
CAUSES OF HYPERPROLACTINAEMIA (III) Pharmacological Numerous drugs stimule PRL Antihypertensive drugs : - reserpine, a-methyldopa, verapamil Neuroleptics & antidepressants : - phenothiazines, butyrophenones, IMAO, benzamide, imipramine...
CAUSES OF HYPERPROLACTINAEMIA (IV) Pharmacological Antiemetics : metoclopramide, domperidone Hormones : estrogens (high dosage), TRH Opiates Anti-histaminic : cimetidine Anti-tbc : isoniazide
CAUSES OF HYPERPROLACTINAEMIA (V) Pathological Prolactinomas Mixed pituitary adenomas : GH + PRL Defective hypothalamic dopamine secretion or transport to the lactotroph : - Hypothalamic tumors - Pituitary tumors (pseudoprolactinoma) - Trauma (stalk section) - Radiotherapy sequellae
CAUSES OF HYPERPROLACTINAEMIA (VI) Stimulation of the lactotroph : - hypothyroidism (TRH) Other causes : - renal failure - liver cirrhosis - diseases of the chest wall -PCOS Macroprolactinaemia (Big - Big PRL)
INVESTIGATIONS OF HYPERPROLACTINAEMIA When a hyperprolactinaemia is suspected, before further and expensive investigations are proposed, it is necessary to - Obtain a careful history of drug intake - Eliminate a primary hypothyroidism - Control kidney and liver functions - In women with recent onset of amenorrhea or galactorrhea : pregnancy test
DIAGNOSIS OF HYPERPROLACTINAEMIA Basal PRL levels Values >400 ng/ml are virtually diagnostic of prolactinoma Values between 100 and 300 ng/ml are usually caused by a prolactinoma which is radiological evident If PRL values < 100 ng/ml : can be difficult! There is generally a good correlation between PRL levels and the size of the adenoma
TRH TEST FOR PRL 200 µg TRH i.v. Normal response : increase of PRL by > 100 % Prolactinoma : no increase, or less than 30 % (macro) and less than 51 % (micro) But does not exclude all forms of functional hyperprolactinaemia
INVESTIGATIONS OF PROLACTINOMAS Basal PRL levels TRH stimulation test on PRL (if doubts) In case of macroadenoma : test other anterior pituitary functions Imaging Visual field